In bone marrow transplants, stem cells residing in the donors' bone marrow are mobilized to the blood using drug in order to facilitate collection. “Our new method of harvesting stem cells requires only a single injection and mobilizes the cells needed in 15 minutes; so in the time it takes to boil an egg, we are able to acquire the number of stem cells produced by the current standard five-day protocol,” said Jonathan Hoggatt, PhD, principal faculty member of the HSCI, member of the MGH Cancer Center and Center for Transplantation Sciences, and lead author of the Cell paper. “This means less pain, time off work and lifestyle disruption for the donor; more convenience for the clinical staff, and more predictability for the harvesting procedure.”

Currently, the most common way of collecting hematopoietic (blood system) stem cells requires donors to receive daily injections of a drug called G-CSF, which induces stem cells to pass from the bone marrow into the circulation. After five days of injections—which can produce adverse effects ranging from bone pain, to nausea and vomiting, to enlargement or rupture of the spleen—the stem cells are collected through the bone marrow donation process of apheresis, which takes four to five hours. Sometimes more than one apheresis is required to collect enough stem cells, particularly when patients with conditions like multiple myeloma or non-Hodgkin’s lymphoma are donating their own cells.

Louis Pelus, PhD, Professor of Microbiology and Immunology at Indiana University School of Medicine and senior author of the current study, had previously found that a protein called GRO (growth regulated oncogene)-beta induced rapid movement of stem cells from the marrow into the blood in animal models. Initial experiments by the current study’s team revealed that GRO-beta injections were safe and well tolerated in human volunteers but had only a modest effect in mobilizing stem cells. As a result, they used mice to test the combination of GRO-beta with AMD3100, a drug that is already approved to increase stem cell mobilization in combination with G-CSF. They found that simultaneous administration of both drugs rapidly produced a quantity of cells equal to that provided by the five-day G-CSF protocol.

In addition to determining the mechanisms by which combined administration of GRO-beta and AMD3100 produced enough stem cells so quickly, the team found that transplantation with these cells led to faster reconstitution of bone marrow and recovery of immune cell populations in mouse models. The stem cells produced by this procedure also showed patterns of gene expression similar to those of fetal hematopoietic stem cells (HSCs), which are located in the liver, rather than the bone marrow.

“These highly engraftable hematopoietic stem cells produced by our new strategy are essentially the A+ students of bone marrow stem cells,” said Hoggatt. “Finding that they express genes similar to those of fetal liver HSCs, the blood-producing cells you have before birth, suggests that they will be very good at moving into an empty bone marrow space and rapidly dividing to fill the marrow and produce blood. Now we need to test the combination in a clinical trial to confirm its safety and effectiveness in humans.”

Hoggatt added that these new, highly engraftable HSCs and the protocol that generated them represent a valuable approach that could lead to new ways of engineering cells that are even better at engrafting and to new methods of expanding stem cells.

“This is an exciting time in bone marrow transplantation, as the number of diseases that can be treated or possibly even cured is increasing,” he said. “With new gene therapy strategies being developed for diseases like sickle cell anemia, beta thalassemia and severe combined immunodeficiency—the ‘bubble boy disease’—having enough high-quality, gene-altered cells can be a key bottleneck. Our ability to acquire highly engraftable HSCs with the GRO-beta and AMD3100 combination should significantly improve and expand the availability of those treatments.”

Support for this study includes National Institutes of Health grants R00 HL119559, R01 HL069669, R01 HL096305 and R01 HL131768 and support from GlaxoSmithKline and the Massachusetts Life Sciences Center. A patent application covering intellectual property described in this paper has been filed by Harvard Office of Technology Development, and Magenta Therapeutics of Cambridge, co-founded by Hoggatt and Scadden, is exploring further clinical development.

About Harvard Stem Cell Science

Advancing Biomedicine From Classroom to ClinicThe Harvard Stem Cell Institute and Harvard Department of Stem Cell and Regenerative Biologyadvance the understanding of human development and disease, support the discovery of stem cell-based therapies and cures for diseases, create collaborations across traditional institutional and disciplinary boundaries, and teach and train the next generation of leading stem cell scientists.